Voclosporin plus standard care boosts 1-year renal response in lupus nephritis
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Voclosporin, when added to mycophenolate mofetil and low-dose steroids, results in higher complete renal response rates in patients with lupus nephritis, compared with mycophenolate mofetil and low-dose steroids alone, according to data.
“The addition of calcineurin inhibitors (CNIs) to an immunosuppressive regimen in studies of predominantly Asian patients with lupus nephritis has been shown to improve renal response rates with a lower dose of steroids and mycophenolate mofetil (MMF) than used conventionally,” Brad H. Rovin, MD, of the Ohio State University Wexner Medical Center, in Columbus, and colleagues wrote in The Lancet. “The general applicability of these data was not clear because the CNI regimen had not been tested in ethnically and racially diverse patients with lupus nephritis.”
“Voclosporin, a novel CNI developed for the treatment of lupus nephritis, has several advantages compared with traditional CNIs,” they added. “These include a consistent pharmacokinetic profile eliminating the need for therapeutic drug monitoring required for other CNIs and a more favorable effect on lipids and glucose concentrations compared with other CNIs. Additionally, voclosporin has no effect on concentrations of mycophenolic acid, the active moiety of MMF.”
In a randomized controlled phase 2 trial, 23.7 mg of voclosporin (Lupkynis, Aurinia Pharmaceuticals), administered twice daily and in combination with MMF and rapidly tapered low-dose oral steroids, resulted in significantly higher complete renal response rates at 24 and 48 weeks, according to the researchers.
To further evaluate the safety and efficacy of voclosporin 23.7 mg in patients with lupus nephritis, Rovin and colleagues conducted the phase 3 AURORA 1 study, a double-blind, randomized trial of 357 participants from 142 hospital across 27 countries. Eligibility criteria included a diagnosis of lupus nephritis and a kidney biopsy within 2 years that demonstrated class III, IV or V. Between April 13, 2017, and Oct. 10, 2019, a total of 179 patients were assigned to receive 23.7 mg of voclosporin twice daily, while 178 were placed in the placebo group.
All participants were treated with a background of 1 mg of MMF twice daily and rapidly tapered low-dose oral steroids. The primary endpoint was complete renal response at 52 weeks, defined as a composite of urine protein creatinine ratio of 0.5 mg/mg or less, stable renal function, no rescue medication, and no more than 10 mg of prednisone equivalent per day for 3 or more consecutive days, or for 7 or more days during weeks 44 through 52, prior the primary endpoint assessment. The researchers assessed safety throughout the trial.
According to the researchers, 41% of participants in the voclosporin group achieved complete renal response at week 52, compared with 23% for those who received a placebo (OR = 2.65; 95% CI 1.64-4.27). Meanwhile, serious adverse events occurred in 21% of both groups. The most frequent serious adverse event involving infection was pneumonia, which developed in 4% of participants in both groups. Six patients died during the study or study follow-up period, including one from the voclosporin group and five in the placebo group. The researchers concluded that none of the deaths were related to the study treatments.
“The AURORA 1 study validates the importance of Lupkynis in early disease intervention for lupus nephritis (LN),” Robert Huizinga, PhD, study co-author and executive vice president of research at Aurinia Pharmaceuticals, told Healio Rheumatology. “The data demonstrate that the therapy is an efficacious, safe, and rapid-acting treatment option. This study supports the clinical value of Lupkynis, and we look forward to continuing to bring this new therapy to LN patients.”
“In the AURORA 1 study, Lupkynis met its primary endpoint, achieving a statistically significant complete renal response rates at 52 weeks, which is important given the urgency in treating LN and did so more quickly than the control arm,” he added. “If poorly controlled, LN can lead to permanent and irreversible tissue damage within the kidney, which makes LN a life-threatening condition, and from what we have seen in our clinical trials, not only is Lupkynis effective in treating LN, but also protects the kidneys from further damage.”
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
The calcineurin inhibitor saga is an interesting one. Cyclosporine was first discovered in 1976 by scientists at Sandoz (now Novartis). It was a breakthrough in modern medicine, revolutionizing organ transplantation, and remains a mainstay 45 years since its discovery. Cyclosporine was originally derived from the filamentous fungus Tolypocladium inflatum Gams in the antibiotic screening program at Sandoz.
Ten years later, scientists at Fujisawa Pharmaceuticals discovered a macrolide antibiotic from a soil fungus that was later named tacrolimus. Voclosporin, a more potent derivative of cyclosporine, was discovered in 1993 by scientists in Edmonton, Alberta at Isotechnika (now Aurinia). Cyclosporine, tacrolimus, and voclosporin share the same pharmacodynamic property of activated T cell suppression via inhibition of calcineurin.
Voclosporin has been studied extensively in patients with immunologic disorders such as psoriasis, organ transplantation, uveitis and lupus nephritis. In all these patients with immunologic disorders, voclosporin demonstrated better tolerability and lack of nephrotoxicity. Voclosporin was highly efficacious in lupus nephritis, yet inferior to cyclosporine in treating psoriasis and noninferior to tacrolimus in organ transplantation. Voclosporin has greater potency for calcineurin inhibition at a 10-fold lower dosing than cyclosporine (20-40 mg once daily compared to 200-600 mg once daily for cyclosporine) with resultant reduced renal and cardiovascular toxicity.
The psoriasis trials, although negative for voclosporin, revealed that voclosporin exhibited lower rates of hypertension of 7-10% while cyclosporine had significantly higher rates of hypertension at 25-28%; there were also significant differences in neurotoxicity and gastrointestinal toxicity between the agents. As rheumatologists, we are pleased to have an additional weapon in our fight against lupus nephritis.
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